CGRP Antagonists the Next Frontier for Migraine Prevention

Megan Brooks

November 30, 2017

Two investigational monoclonal antibodies that target calcitonin gene-related peptide (CGRP) proved safe and effective for migraine prevention in separate randomized placebo-controlled phase 3 studies published November 30 in the New England Journal of Medicine.

One is erenumab (AMG334, Amgen/Novartis), a fully human monoclonal antibody targeting CGRP receptor, and the other is fremanezumab (TEV-48125, Teva Pharmaceuticals), a humanized monoclonal antibody targeting CGRP itself.

Mechanism-Specific Treatment

CGRP is a neuropeptide believed to be directly involved in the pathophysiologic processes underlying migraine.  Targeting CGRP is a "new distinct treatment and what we call a mechanism-specific treatment in the sense that CGRP may be the mechanism of migraine," Stephen Silberstein, MD, from the Jefferson Headache Center at Thomas Jefferson University in Philadelphia, Pennsylvania, noted in an interview with Medscape Medical News.

In the fremanezumab trial,  Dr Silberstein and colleagues enrolled 1130 patients with chronic migraine (defined as headache of any duration or severity on 15 or more days per month and migraine on 8 days or more per month). Patients were randomly allocated to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8; n = 376), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8; n = 379), or matching placebo (n = 375). Both fremanezumab and placebo were given by subcutaneous injection.

Baseline demographic and clinical characteristics were similar among the three groups; the mean number of baseline headache days per month was 13.2 in the fremanezumab-quarterly group, 12.8 in the fremanezumab-monthly group, and 13.3 in the placebo group.

Results showed a significant benefit of fremanezumab over placebo with regard to the average number of headache days per month, which was reduced by 4.3 days with fremanezumab quarterly and 4.6 days with fremanezumab monthly, vs 2.5 days with placebo (P < .001 for both comparisons with placebo).

There was also a significantly larger reduction in the average number of migraine days per month with fremanezumab quarterly (by 4.9 days) and monthly (by 5.0 days) than with placebo (by 3.2 days; P < .001 for both comparisons with placebo).

In addition, significantly more patients who received fremanezumab had a reduction of at least 50% in the average number of headache days per month (38% with the quarterly regimen and 41% with the monthly regimen) than did patients who received placebo (18%) (P < .001 for both comparisons with placebo).

Fremanezumab "has a lasting effect that starts immediately, within a couple days," Dr Silberstein told Medscape Medical News. "And when patients respond they often respond extraordinarily well.  So it works quickly and it's effective and has no more side effects than placebo except that it hurts at the site of injection," he noted. 

In the erenumab trial,  Peter Goadsby, MD, PhD, from King's College London, United Kingdom, and colleagues randomly assigned 955 patients with episodic migraine to receive a subcutaneous injection of erenumab 70 mg (n = 317) or 140 mg (n = 319) or placebo (n = 319) monthly for 6 months.

At baseline, the average number of migraine days per month was 8.3 in the overall population. By months 4 through 6, the number was reduced by 3.2 days in the 70-mg erenumab group and by 3.7 days in the 140-mg erenumab group, compared with 1.8 days in the placebo group (P < .001 for each dose vs placebo).

A 50% or greater reduction in the average number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P < .001 for each dose vs placebo).

In addition, the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P < .001 for each dose vs placebo).

Patients receiving erenumab reported reduced physical impairment and improved ability to participate in daily activities, according to a validated patient-reported outcome tool. Rates of adverse events were similar between erenumab and placebo.

Important Advance in Migraine

Both erenumab and fremanezumab have been submitted to the US Food and Drug Administration for approval. Two other antibodies targeting the CGRP pathway for migraine prevention are also in development. They are eptinezumab (Alder Biopharmaceuticals) and galcanezumab (Eli Lilly & Co).

"With the ongoing development of four different antibodies targeting the CGRP pathway, it will be difficult to determine whether unique patient populations will have a response to a specific drug or whether one agent is superior to others," Andrew Hershey, MD, PhD, from University of Cincinnati College of Medicine in Ohio, writes in an editorial.

"Furthermore, many patients will probably still have a response to standard multidisciplinary treatment that is less costly in patient and provider time and dollars. It is of interest that these agents worked rapidly and that a number of patients became completely headache-free. Thus, these drugs may find a specific role in the treatment of patients who have migraines that are refractory to treatment or who are severely disabled by headaches," he notes.

Dr Hershey says it will also be important to determine whether the beneficial effects are sustained after discontinuation or whether continued treatment will be necessary.

"A migraine-specific preventive treatment that is directed toward a suspected underlying pathophysiological mechanism is an important advance for patients with migraine. As mechanisms of migraine are revealed by advances in neuroimaging, biomarker identification, and genomic analysis, one may expect new compounds to bring a brighter future to our patients who have migraine," Dr Hershey concludes.

The fremanezumab trial was funded by Teva Pharmaceuticals, and the erenumab trial was funded by Amgen and Novartis. Full disclosures for authors are available with the full text of the articles at NEJM.org.

N Engl J Med. 2017;377:2113-2122, 2123-2132, 2190-2191.  Silberstein et al abstract,  Goadsby et al abstract,  Editorial  

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